Warning(s)

Serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), may occur if quinine is used for treatment or prevention of nocturnal leg cramps†.180

Known risks associated with use of quinine, in the absence of evidence of safety and efficacy of the drug for treatment or prevention of nocturnal leg cramps†, outweigh any potential benefits for this unlabeled indication.180

(See Use for Treatment or Prevention of Nocturnal Leg Cramps under Cautions.)

REMS:

FDA approved a REMS for quinine sulfate to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of quinine sulfate and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Uses for Qualaquin

Treatment of Uncomplicated Malaria

Treatment of uncomplicated Plasmodium falciparum malaria.165171180186 Also used for treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax†165171173186 and for treatment of uncomplicated malaria when plasmodial species has not been identified†.165171173186

Designated an orphan drug by FDA for the treatment of malaria.179 Since malaria is a life-threatening infection, FDA states that the potential benefits of the drug outweigh the associated risks and justify its use for the treatment of malaria.182

For treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum in nonpregnant adults and children ≥8 years of age† and for treatment of uncomplicated malaria in this age group when plasmodial species not identified and the disease was acquired in areas with chloroquine resistance†, CDC recommends the fixed combination of atovaquone and proguanil (Malarone); the fixed combination of artemether and lumefantrine (Coartem); or a regimen that includes quinine in conjunction with doxycycline, tetracycline, or clindamycin.171186 Because of serious adverse effects (e.g., severe neuropsychiatric reactions), use mefloquine only if the recommended treatment regimens cannot be used.171186 If a quinine regimen is used, concomitant doxycycline or tetracycline generally preferred instead of concomitant clindamycin since more efficacy data exist regarding antimalarial regimens that include tetracyclines.171186

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax† in nonpregnant adults and children ≥8 years of age†, CDC recommends a regimen of quinine and doxycycline (or tetracycline) given in conjunction with primaquine; the fixed combination of atovaquone and proguanil (Malarone) given in conjunction with primaquine; or mefloquine given in conjunction with primaquine.171186 Primaquine is necessary in these regimens to provide a radical cure and prevent relapse of P. vivax malaria.165171186

In children <8 years of age with chloroquine-resistant P. falciparum malaria or when the plasmodial species has not been identified and the disease was acquired in areas with chloroquine resistance, CDC recommends the fixed combination of atovaquone and proguanil (Malarone) or fixed combination of artemether and lumefantrine (Coartem); mefloquine can be considered if no other options are available.186 If a quinine regimen is used in children <8 years of age†, CDC states that quinine monotherapy may be given for 7 days or a regimen of quinine and clindamycin can be given for the usually recommended duration.171 Alternatively, CDC states that a regimen of quinine and doxycycline or tetracycline can be considered in children <8 years of age† in rare circumstances when other treatment options are not available or not tolerated and the benefits of including a tetracycline in the regimen are judged to outweigh risks.171 In children <8 years of age with chloroquine-resistant P. vivax malaria, CDC recommends mefloquine in conjunction with primaquine as the regimen of choice; if mefloquine is not available or not tolerated and if benefits outweigh risks, the fixed combination of atovaquone and proguanil or fixed combination of artemether and lumefantrine can be used as alternatives. 171186

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In pregnant women with uncomplicated malaria, CDC recommends a regimen of quinine and clindamycin for infections caused by chloroquine-resistant P. falciparum and a regimen of quinine for infections caused by chloroquine-resistant P. vivax†.171186 (See Pregnancy under Cautions.) Although tetracyclines generally are contraindicated in pregnant women, in rare circumstances (e.g., other treatment options not available or not tolerated), CDC states that quinine may be used in conjunction with doxycycline or tetracycline for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or P. vivax in pregnant women if benefits outweigh risks.171186

Assistance with diagnosis or treatment of malaria is available from CDC Malaria Hotline at 770-488-7788 from 8:00 a.m. to 4:30 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays.171

Treatment of Severe Malaria

Severe malaria usually is caused by P. falciparum and requires initial aggressive treatment with a parenteral antimalarial regimen initiated as soon as possible after diagnosis.171186200 Also can consider exchange transfusions if parasitemia is >10% or patient has cerebral malaria, altered mental status, nonvolume overload pulmonary edema, or renal complications and if potential benefits outweigh risks.186200

For treatment of severe malaria in adults and children, CDC recommends an initial regimen of IV quinidine in conjunction with doxycycline, tetracycline, or clindamycin (administered orally or IV as tolerated).171186 After parasitemia is reduced to <1% and oral therapy is tolerated, IV quinidine can be discontinued and oral quinine initiated to complete 7 or 3 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).171186

If IV quinidine is unavailable or cannot be used for initial treatment because of adverse effects or contraindications, parenteral artesunate is available from CDC under an investigational new drug (IND) protocol for emergency initial treatment of severe malaria.171186

Assistance with diagnosis or treatment of malaria and assistance obtaining quinidine or artesunate for treatment of severe malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 from 8:00 a.m. to 4:30 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays.171

Presumptive Self-treatment of Malaria

A regimen of quinine in conjunction with doxycycline has been recommended by some clinicians for presumptive self-treatment of malaria† in travelers.165

Not approved by FDA for presumptive self-treatment of malaria in travelers180 and not recommended by CDC or other clinicians for such treatment.164200

For presumptive self-treatment of malaria in travelers, CDC recommends the fixed combination of atovaquone and proguanil (Malarone) in those not already taking the drug for prevention of malaria.164 Contact CDC Malaria Hotline (770-488-7788) for information regarding other potential options for self-treatment if atovaquone and proguanil cannot be used.164

Prevention of Malaria

Not approved by FDA for prevention (prophylaxis) of malaria180 and not included in current CDC recommendations for prevention of malaria.164

CDC and other clinicians recommend use of other antimalarial agents (e.g., chloroquine [or hydroxychloroquine], mefloquine, doxycycline, fixed combination of atovaquone and proguanil hydrochloride) for prevention of malaria caused by susceptible plasmodia.164165166168169

Detailed recommendations regarding prevention of malaria are available from the CDC 24 hours a day from the voice information service (877-394-8747) or CDC website ().164

Babesiosis

IDSA states that all patients with active babesiosis (i.e., symptoms of viral-like infection and identification of babesial parasites in blood smears or by polymerase chain reaction [PCR] amplification of babesial DNA) should receive anti-infective treatment because of the risk of complications; however, symptomatic patients whose serum contains antibody to babesia but whose blood lacks identifiable babesial parasites on smear or babesial DNA by PCR should not receive treatment.178 Treatment is not recommended initially for asymptomatic individuals, regardless of results of serologic examination, blood smears, or PCR, but should be considered if parasitemia persists for >3 months.178

When anti-infective treatment of babesiosis is indicated, IDSA and other clinicians recommend a regimen of quinine and clindamycin or a regimen of atovaquone and azithromycin.165169178181

The quinine and clindamycin regimen may be preferred for severe babesiosis.178 However, there is some evidence that, in patients with mild or moderate illness, the atovaquone and azithromycin regimen may be as effective and better tolerated than the quinine and clindamycin regimen.165169178181 Consider use of exchange transfusions, especially in severely ill patients with high levels of parasitemia (≥10%), significant hemolysis, or compromised renal, hepatic, or pulmonary function.165169178

B. microti is transmitted by Ixodes scapularis ticks, which also may be simultaneously infected with and transmit Borrelia burgdorferi (causative agent of Lyme disease) and Anaplasma phagocytophilum (causative agent of human granulocytotropic anaplasmosis [HGA, formerly known as human granulocytic ehrlichiosis]).169178 Consider possibility of coinfection with B. burgdorferi and/or A. phagocytophilum in patients who have severe or persistent symptoms despite appropriate anti-infective treatment for babesiosis.178

Nocturnal Recumbency Leg Muscle Cramps

Not approved by FDA for the treatment or prevention of nocturnal leg cramps†.180182185187 Should not be used in the management of this or related conditions (e.g. restless legs syndrome†).180182185187201

Although quinine has been used in the past for the prevention and treatment of nocturnal recumbency leg muscle cramps† (night cramps),175176177182184185198 there are no adequate and well-controlled studies evaluating efficacy and safety for this use.119120121122124154155184185

Quinine has a narrow margin of safety and may cause unpredictable serious and life-threatening hypersensitivity reactions, QT interval prolongation, serious cardiac arrhythmias (including torsades de pointes), serious hematologic reactions (including thrombocytopenia and HUS/TTP), and other serious adverse events (e.g., blindness, deafness) requiring medical intervention and hospitalization.180184185187188191193201 Fatalities associated with use of the drug have been reported.180185187201 (See Cautions.) The known risks associated with the use of quinine, in the absence of evidence of safety and efficacy of the drug for the treatment or prevention of nocturnal leg cramps†, outweigh any potential benefits for this benign, self-limiting condition.180184185187

FDA has determined that quinine preparations (including preparations containing any quinine salt alone or in fixed combination with vitamin E) are not generally recognized as safe and effective for treatment or prevention of nocturnal leg muscle cramps.185 Promotion of quinine for self-medication of nocturnal leg cramps has been prohibited in the US since February 1995 because of safety concerns.154155184185 In addition, FDA ordered that marketing of all unapproved quinine preparations be discontinued as of December 11, 2006.182 (See Preparations.)

Qualaquin Dosage and Administration

Administration

Although quinine has been administered by slow IV infusion as quinine dihydrochloride, a parenteral preparation of the drug no longer is available for use in the US, either commercially or from CDC.148149 When parenteral antimalarial therapy is indicated, use IV quinidine gluconate.148149171186

Oral Administration

May be administered without regard to meals.180 Administration with food recommended to minimize possible GI irritation.165180

Dosage

Available as quinine sulfate; dosage expressed in terms of the salt.180

The only FDA-approved preparation of quinine currently commercially available in the US is a capsule containing 324 mg of quinine sulfate (Qualaquin; distributed by AR Scientific, Inc); the drug was previously available in the US as capsules containing 325 mg.180185 This difference in quinine preparations may result in minor disparities between some published dosage recommendations that were based on the previously available 325-mg capsules and dosage recommendations for the currently available 324-mg capsules.a

Pediatric Patients

Malaria

Treatment of Uncomplicated Malaria Caused by Chloroquine-resistant P. falciparum or Unidentified Plasmodial Species

Oral

Children ≥8 years of age†: 10 mg/kg 3 times daily for 7 or 3 days as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).165 Use in conjunction with a 7-day regimen of oral doxycycline, tetracycline, or clindamycin.165186

Children <8 years of age†: If a quinine regimen is used, CDC states quinine monotherapy may be given for 7 days or quinine can be given in conjunction with clindamycin for the usually recommended duration.171 In rare circumstances, a regimen of quinine and doxycycline or tetracycline can be considered.171 (See Treatment of Uncomplicated Malaria under Uses.)

Children ≥8 years of age†: 10 mg/kg 3 times daily for 7 or 3 days as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).165 Do not exceed usual adult dosage.171186

Use in conjunction with a 7-day regimen of oral doxycycline or tetracycline and a 14-day regimen of oral primaquine.165186 Primaquine is necessary to provide a radical cure and prevent relapse of P. vivax malaria.165171186

10 mg/kg 3 times daily to complete 7 or 3 days of total IV quinidine and oral quinine therapy as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).199 Do not exceed usual adult dosage.171

IV quinidine gluconate must be used initially; after ≥24 hours and after parasitemia is reduced to <1% and oral therapy is tolerated, oral quinine may be substituted.186

Use quinidine/quinine regimen in conjunction with a 7-day regimen of doxycycline, tetracycline, or clindamycin (administered IV or orally as tolerated).186

10 mg/kg 3 times daily for 7 or 3 days as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere) given in conjunction with a 7-day regimen of oral doxycycline.165

Not included in current CDC recommendations for presumptive self-treatment of malaria in travelers.164

Oral

Other clinicians recommend 30 mg/kg daily in 3 divided doses given for 7–10 days in conjunction with oral clindamycin (20–40 mg/kg daily in 3 divided doses for 7–10 days).165

For mild to moderate babesiosis, clinical improvement should be evident within 48 hours after initiation of treatment and symptoms should resolve completely within 3 months.178 Low-grade parasitemia may persist in some patients for months after completion of treatment.178 Regardless of presence or absence of symptoms, IDSA suggests that retreatment be considered if babesial parasites or amplifiable babesial DNA is detected in blood ≥3 months after initial treatment.178

Adults

Malaria

Treatment of Uncomplicated Malaria Caused by Chloroquine-resistant P. falciparum or Unidentified Plasmodial Species

Oral

Manufacturer recommends 648 mg every 8 hours for 7 days for P. falciparum malaria.180 Manufacturer cautions that shorter regimens (3 days) have been used, but data regarding these regimens are limited and they may be less effective than a 7-day regimen.180

CDC and other clinicians recommend 650 mg (two 324-mg capsules) every 8 hours for 7 or 3 days as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).165186 Use in conjunction with a 7-day regimen of oral doxycycline, tetracycline, or clindamycin.165171186

Pregnant women: CDC recommends 650 mg (two 324-mg capsules) every 8 hours for 7 or 3 days as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).186 Use in conjunction with a 7-day regimen of oral clindamycin.171186 Alternatively, if benefits outweigh risks, used in conjunction with oral doxycycline or tetracycline.186

650 mg (two 324-mg capsules) every 8 hours for 7 or 3 days as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).165186 Use in conjunction with a 7-day regimen of oral doxycycline or tetracycline and a 14-day regimen of oral primaquine.165171 Primaquine is necessary to provide a radical cure and prevent relapse of P. vivax malaria.165171186

Pregnant women: CDC recommends 650 mg (two 324-mg capsules) every 8 hours for 7 days (regardless of where infection was acquired).186 Used alone171186 or, if benefits outweigh risks, used in conjunction with oral doxycycline or tetracycline.186 Then, give chloroquine (300 mg [500 mg of chloroquine phosphate] once weekly) as prophylaxis for the duration of the pregnancy until primaquine can be given after delivery to provide a radical cure and prevent relapse.171186

650 mg (two 324-mg capsules) every 8 hours to complete 7 or 3 days of total IV quinidine and oral quinine therapy as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if acquired elsewhere).186

IV quinidine gluconate must be used initially; after ≥24 hours and after parasitemia is reduced to <1% and oral therapy is tolerated, oral quinine may be substituted.186

Use quinidine/quinine regimen in conjunction with a 7-day regimen of doxycycline, tetracycline, or clindamycin (administered IV or orally as tolerated).186

Oral

IDSA and other clinicians recommend 650 mg every 6–8 hours in conjunction with clindamycin (300–600 mg IV every 6 hours or 600 mg orally every 8 hours) given for 7–10 days.165178

For mild to moderate babesiosis, clinical improvement should be evident within 48 hours after initiation of treatment and symptoms should resolve completely within 3 months.178 Low-grade parasitemia may persist in some patients for months after completion of treatment.178 Regardless of presence or absence of symptoms, IDSA suggests that retreatment be considered if babesial parasites or amplifiable babesial DNA is detected in blood ≥3 months after initial treatment.178

Pediatric Patients

Treatment of Uncomplicated or Severe Malaria

Oral

Babesiosis

Oral

Special Populations

Hepatic Impairment

Treatment of Uncomplicated Malaria

Reduced dosage not necessary in adults with mild to moderate hepatic impairment (Child-Pugh class A or B).180 Monitor such patients closely for adverse effects.180

Safety and pharmacokinetics in patients with severe hepatic impairment (Child-Pugh class C) not determined to date.180

Renal Impairment

Treatment of Uncomplicated Malaria

For adults with severe chronic renal failure, computer models indicate dosage should be modified to include a 648-mg loading dose followed 12 hours later by maintenance doses of 324 mg given every 12 hours.180

Safety and pharmacokinetics in patients with mild or moderate renal impairment not determined to date.180

Quinine is not approved by FDA for treatment or prevention of nocturnal leg cramps†, and should not be used in the management of this or related conditions (e.g., restless legs syndrome†).180182185187201 The known risks associated with use of quinine, in the absence of evidence of safety and efficacy of the drug for treatment or prevention of nocturnal leg cramps†, outweigh any potential benefits for this benign, self-limiting condition.180184185187

FDA has determined that quinine preparations (including preparations containing any quinine salt alone or in fixed combination with vitamin E) are not generally recognized as safe and effective for treatment or prevention of nocturnal leg muscle cramps†.185 Promotion of quinine for self-medication of nocturnal leg cramps† has been prohibited in the US since February 1995 because of safety concerns.154155184185

Because of serious safety concerns, FDA initiated several regulatory actions in December 2006 to remove unapproved quinine preparations from the US market.182185187 Despite these efforts, quinine still is being prescribed for uses other than malaria, and FDA continues to receive reports of serious adverse effects associated with the drug.187

Because of continued reports of serious adverse effects in patients using quinine for unlabeled indications, the FDA required and approved a REMS for quinine sulfate in 2010.201202 The goals of the quinine REMS are to inform patients and health-care providers about the serious and life-threatening hematologic adverse events (thrombocytopenia and HUS/TTP) associated with use of quinine in the treatment or prevention of nocturnal leg cramps†.202 The REMS requires that a quinine medication guide be provided to the patient each time the drug is dispensed and outlines a communication plan requiring initial and subsequent communications from the manufacturer to targeted groups of prescribers.202

Hematologic Effects

Serious, life-threatening, and sometimes fatal hematologic reactions, including thrombocytopenia144180188201 and HUS/TTP,180201 have been reported in patients receiving quinine, especially those using the drug for unlabeled indications (prevention or treatment of leg cramps or restless leg syndrome†).187201 Subsequent development of chronic renal impairment has occurred in patients with quinine-associated TTP.180201

In 24 reported cases of serious hematologic reactions, median time to onset was approximately 2 weeks after initiation of quinine.201 Most recovered when the drug was discontinued and other therapeutic interventions initiated, but there were 2 fatalities (one related to TTP and the other related to hemolysis).201

If thrombocytopenia occurs, discontinue quinine since continued therapy puts patient at risk for fatal hemorrhage.180 Thrombocytopenia usually resolves within 1 week after quinine is discontinued.180 Quinine-induced thrombocytopenia is immune-mediated and re-exposure to quinine from any source may result in a more rapid and more severe course of thrombocytopenia compared to original episode.180

QT Prolongation and Other Cardiovascular Effects

QT interval prolongation has been reported in most studies evaluating oral or parenteral quinine and has occurred independent of the patient’s age, clinical status, or disease severity.180 Maximal increases in QT interval correlate with peak plasma quinine concentrations.180

Do not use in patients with known prolonged QT interval.180 Avoid use in patients with clinical conditions known to prolong the QT interval (e.g., uncorrected hypokalemia, bradycardia, certain cardiac conditions) and in those receiving other drugs known to cause QT prolongation.180 (See Drugs that Prolong the QT Interval under Interactions.)

Use caution in patients with atrial fibrillation or atrial flutter.180 A paradoxical increase in ventricular response rate may occur with quinine, similar to that observed with quinidine.180 Monitor closely if digoxin is used to prevent a rapid ventricular response.180 (See Digoxin under Interactions.)

Avoid use with drugs that are CYP3A4 substrates and are known to cause QT prolongation (e.g., cisapride [available in the US only under a limited-use protocol], pimozide, halofantrine [not commercially available in the US], quinidine).180 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

G-6-PD Deficiency

Potential for hemolysis and hemolytic anemia if used in patients with G-6-PD deficiency.180 Discontinue immediately if evidence of hemolysis occurs.180

Photosensitivity Reactions

General Precautions

Cinchonism

A cluster of symptoms referred to as “cinchonism” occurs in practically all patients receiving quinine.180 Most manifestations of cinchonism are reversible and resolve following discontinuance of quinine.180

Specific Populations

Pregnancy

Crosses the placenta.180 Although quinine concentrations may be measurable in the fetus and cord blood of women who received the drug near the time of delivery (see Distribution under Pharmacokinetics), such concentrations may not be therapeutic for the fetus.180 If congenital malaria is suspected, evaluate the infant after delivery and treat with antimalarial agents if appropriate.180

Deafness and optic nerve hypoplasia have been reported rarely in children exposed in utero when the mother received high-dose quinine therapy during pregnancy.180

In animal studies evaluating sub-Q or IM quinine, teratogenic effects were demonstrated in some animal species, but not in others.180 In a study in women with P. falciparum malaria who received a 7-day regimen of oral quinine during various stages of pregnancy, there was no difference in the rate of stillbirths at >28 weeks of gestation or overall rate of congenital malformations compared with a control group without malaria or treatment with antimalarial agents during pregnancy.180 In addition, the rate of spontaneous abortion was higher in the women without malaria or treatment with antimalarial agents during pregnancy than in the women treated with quinine during pregnancy.180 In an epidemiologic survey, there was no increased risk of structural birth defects in 104 mother-child pairs exposed to quinine during the initial 4 months of gestation.180 Although published data of >1000 pregnancies exposed to quinine (majority of exposures occurred after first trimester) have not shown an increase in teratogenic effects over that of background rates in the general population, there are few well-controlled studies to date evaluating the drug in pregnant women.180

Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with quinine use, especially in pregnant women.180

There is no evidence to date that quinine causes uterine contractions at dosages recommended for the treatment of malaria.180 However, doses several fold higher than those used to treat malaria may stimulate the pregnant uterus.180

CDC recommends the use of quinine for the treatment of uncomplicated chloroquine-resistant P. falciparum or P. vivax malaria in pregnant women.171186 (See Treatment of Uncomplicated Malaria under Uses.) CDC also states that pregnant women diagnosed with severe malaria should be treated aggressively.186 (See Treatment of Severe Malaria under Uses.)

The manufacturer states that quinine should be used during pregnancy only if potential benefits justify potential risks to the fetus and recommends that the risks and benefits of alternative treatments be considered.180

Lactation

Only limited information available regarding safety of quinine in breast-fed infants.180 Although quinine generally considered compatible with breast-feeding, assess the risks and benefits to the infant and mother and use with caution in nursing women.180

Plasma quinine concentrations may not be therapeutic in infants of nursing mothers receiving quinine.180 If malaria is suspected in the infant, provide appropriate evaluation and treatment.180

Pediatric Use

Manufacturer states safety and efficacy not established in children <16 years of age.180

Quinine is included in CDC recommendations for treatment of uncomplicated malaria in pediatric patients†.171186 (See Treatment of Uncomplicated Malaria under Uses.) The drug also is used for follow-up after an initial parenteral antimalarial regimen in children with severe malaria†.199200 (See Treatment of Severe Malaria under Uses.)

Geriatric Use

Clinical studies did not include sufficient numbers of individuals ≥65 years of age to determine whether they respond differently than younger adults.180 Other reported clinical experience has not identified differences in responses between geriatric adults and younger patients.180

Hepatic Impairment

If used in adults with mild to moderate hepatic impairment (Child-Pugh class A or B), monitor closely for adverse effects associated with quinine.180 The effects of severe hepatic impairment (Child-Pugh class C) on safety and pharmacokinetics not determined to date.180

Renal Impairment

Reduced dosage recommended when used for treatment of acute uncomplicated malaria in adults with severe chronic renal failure.180 (See Renal Impairment under Dosage and Administration.) The effects of mild or moderate renal impairment on safety and pharmacokinetics not determined to date.180

Interactions for Qualaquin

Metabolized principally by CYP3A4; may also be metabolized by other CYP enzymes, including 1A2, 2C8, 2C9, 2C19, 2D6, and 2E1.180

Drugs That Prolong the QT Interval

Because quinine prolongs the QT interval, an additive effect on the QT interval might occur if the drug is administered with other drugs that prolong the QT interval.180 Concomitant use of quinine in patients receiving other drugs known to cause QT prolongation, including class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide) and class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide) not recommended.180

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vivo and in vitro drug interaction studies suggest quinine may inhibit metabolism of drugs that are substrates of CYP3A4 and 2D6.180

Avoid use with drugs that are CYP3A4 substrates and are known to cause QT prolongation (e.g., cisapride [available in the US only under a limited-use protocol], pimozide, halofantrine [not commercially available in the US], quinidine).180

Quinine has been shown to decrease metabolism of desipramine in some patients (see Desipramine under Interactions) and may decrease metabolism of some other drugs that are CYP2D6 substrates (e.g., debrisoquine [not commercially available in the US], dextromethorphan, flecainide, methoxyphenamine [not commercially available in the US], metoprolol, paroxetine).180 If used concomitantly with a CYP2D6 substrate, monitor closely for adverse effects associated with the CYP2D6 substrate.180

Drugs Affecting or Affected by P-glycoprotein Transport

Quinine is a substrate for and an inhibitor of P-glycoprotein,180 and has the potential to affect transport of drugs that are P-glycoprotein substrates.180

Phenytoin: No effect on pharmacokinetics of the anticonvulsant;180 possible decreased plasma quinine concentrations180

Carbamazepine or phenobarbital: If concomitant use with quinine cannot be avoided, frequently monitor serum concentrations of the anticonvulsant and monitor closely for anticonvulsant adverse effects180

Decreased quinine AUC and peak plasma concentration when used in malaria patients who were heavy smokers;180 greater effect on quinine pharmacokinetics reported when the drug was given to healthy adults who were heavy smokers180

Smoking does not appear to influence the therapeutic outcome in malaria patients treated with quinine180

Manufacturer of quinine suggests that reduced clearance of quinine in patients with acute malaria (see Elimination under Pharmacokinetics) may diminish the metabolic induction effect of smoking on quinine pharmacokinetics180

Manufacturer states that increased quinine dosage not necessary when treating acute malaria in heavy cigarette smokers180

Desipramine

Decreased metabolism of desipramine in patients who are extensive CYP2D6 metabolizers; no effect in patients who are poor CYP2D6 metabolizers180

Monitor closely for adverse effects if quinine used concomitantly with desipramine180

Carefully weigh benefits and risks if considering concomitant use of quinine and atorvastatin or other HMG-CoA reductase inhibitors that are CYP3A4 substrates (e.g., simvastatin, lovastatin)180

If used concomitantly, consider lower starting and maintenance dosages of the HMG-CoA reductase inhibitor and monitor closely for signs or symptoms of muscle pain, tenderness, or weakness, especially during initial therapy180

Discontinue the HMG-CoA reductase inhibitor if CPK concentrations are markedly elevated or if myopathy (defined as muscle aches or weakness in conjunction with CPK concentrations >10 times the ULN) is diagnosed or suspected180

Use sequentially with caution;146147 because mefloquine has a long serum half-life (15–33 days),147 use caution if initiating quinine for treatment of malaria in patients who were receiving mefloquine for prophylaxis146147

Avoid concomitant use;180 if used concomitantly, quinine dosage may need to be reduced203

Tests, urinary corticosteroids or catecholamines

Quinine causes falsely elevated results when a modification of the Reddy-Jenkins-Thorn procedure is used for urinary 17-hydroxycorticosteroidsa or when the Zimmermann method is used for urinary 17-ketogenic steroids;180 no effect on modified Porter-Silber methoda

Quinine interferes with the Sobel and Henry modification of the trihydroxyindole method for determining urinary catecholamines, resulting in falsely increased concentrationsa

Qualaquin Pharmacokinetics

Absorption

Bioavailability

Oral bioavailability is 76–88% in healthy adults.180 Quinine exposure is higher in patients with malaria than in healthy adults,180 possibly because malaria may cause impaired hepatic function, which results in decreased quinine total body clearance and volume of distribution.106107

In adults with uncomplicated P. falciparum malaria, mean AUC and peak plasma concentrations are higher and time to peak concentration is longer than that reported in healthy adults.180 Following a single oral dose, mean time to peak serum concentrations is 5.9 hours in adults with uncomplicated P. falciparum malaria compared with 2.8 hours in healthy adults.180

Food

When a single 324-mg dose of oral quinine sulfate capsules was administered with a high-fat meal in healthy adults, the time to peak concentrations was prolonged to approximately 4 hours; however, mean peak plasma concentration and AUC from 0–24 hours were similar to those achieved following oral administration of the drug under fasted conditions.180

Special Populations

Pharmacokinetics in children 1.5–12 years of age with uncomplicated P. falciparum malaria appear to be similar to that observed in adults with uncomplicated malaria.180 Following a single dose of 10 mg/kg of oral quinine sulfate in healthy children or children 1.5–12 years of age with uncomplicated P. falciparum malaria, mean time to peak quinine concentration was longer (4 versus 2 hours) and mean peak plasma concentration was higher (7.5 versus 3.4 mcg/mL) in children with uncomplicated P. falciparum malaria than in healthy children.180

Following a single 600-mg dose of oral quinine sulfate, the mean AUC in healthy geriatric adults 65–78 years of age is approximately 38% higher than in younger adults 20–35 years of age;180 mean time to peak quinine concentrations and mean peak plasma concentrations are similar in both age groups.180

Following a single 600-mg dose of oral quinine sulfate in adults with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine 9.6 mg/dL), median AUC and mean peak plasma concentration increased by 195 and 79%, respectively, compared with adults with normal renal function.180 Effect of mild or moderate renal impairment on pharmacokinetics of quinine sulfate not determined to date.180

Following a single 600-mg oral dose of quinine sulfate in otherwise healthy adults with moderate hepatic impairment (Child-Pugh class B), mean AUC is increased 55% compared with healthy adults with normal hepatic function; mean peak plasma concentrations similar in both groups.180 Quinine absorption is prolonged in adults with hepatitis.180 Pharmacokinetic data not available to date for patients with severe hepatic impairment (Child-Pugh class C).180

Distribution

Extent

Volume of distribution is lower in patients with malaria than in healthy individuals or patients convalescing from malaria.106 Volume of distribution decreases with increasing severity of malarial infection.180

Intra-erythrocytic quinine concentrations are approximately 30–50% of plasma concentrations.180 Small amounts distributed into bile and saliva.a

Readily crosses the placenta.180 In a small number of women who delivered live infants 1–6 days after starting quinine therapy, placental cord plasma quinine concentrations were 1–4.6 mg/L (mean: 2.4 mg/L) and mean ratio of cord plasma to maternal plasma quinine concentrations was 0.32.180 Such placental cord concentrations may not result in therapeutic fetal plasma quinine concentrations.180

Plasma Protein Binding

During active malarial infection, protein binding increased to 78–95%, which correlates with increases in α-1-acid glycoprotein that occur during malarial infection.180 In one study, quinine was approximately 93% bound to plasma proteins in patients with cerebral malaria and approximately 90% bound in patients with uncomplicated malaria or in patients convalescing from the disease.106

The major metabolite, 3-hydroxyquinine, is less active than the parent drug.180

In vitro studies indicate quinine is metabolized principally by CYP3A4 and may also be metabolized by other CYP enzymes, including 1A2, 2C8, 2C9, 2C19, 2D6, and 2E1.180

Elimination Route

Approximately 20% of a dose excreted unchanged in urine.180 Reabsorption of quinine is increased when urine is alkaline; rate of renal excretion of the drug is doubled when urine is acidic compared with when urine is alkaline.180

Negligible to minimal amounts removed by hemodialysis or hemofiltration.180

Half-life

Adults: 8–21 hours in those with malaria and 7–12 hours in those who are healthy or convalescing from the disease.106107

Children 1–12 years of age: 11–12 hours in those with malaria and 6 hours in those convalescing from the disease.106

Geriatric adults: Mean elimination half-life is increased to 18.4 hours.180 Although renal clearance of quinine is similar in geriatric and younger adults, geriatric adults excrete a larger proportion of the dose in urine as unchanged drug compared with younger adults.180

Special Populations

Plasma concentrations are higher and plasma half-life may be prolonged in patients with malaria.106107

Adults with hepatitis: Elimination half-life and apparent volume of distribution are increased, but weight-adjusted clearance not altered.180

Stability

Storage

Oral

Capsules

Actions and Spectrum

An alkaloid obtained from the bark of the cinchona tree; the levorotatory isomer of quinidine.185

Has several effects on skeletal muscle.a Increases the refractory period of muscle by a direct action on muscle fiber so that the response to tetanic stimulation is diminished;a has a curare-like effect and decreases the excitability of the motor endplate so that responses to repetitive nerve stimulation or acetylcholine are reduced;a and affects the distribution of calcium within muscle fiber.a

Exact mechanism of antimalarial activity not determined.180 Inhibits nucleic acid synthesis, protein synthesis, and glycolysis in P. falciparum and can bind with hemazoin in parasitized erythrocytes.180

A blood schizonticidal agent active against the asexual erythrocytic forms of P. falciparum,180P. malariae,aP. ovale,a and P. vivax.189 Not gametocidal against P. falciparum.180 Inactive against sporozoites or pre-erythrocytic or exoerythrocytic forms of plasmodia.180

P. falciparum malaria clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh.180 Strains of P. falciparum with decreased susceptibility to quinine also can be selected in vivo.180

Although cross-resistance has been demonstrated rarely between quinine and 4-aminoquinoline derivatives, quinine may be active against some strains of P. falciparum resistant to chloroquine and/or sulfadoxine and pyrimethamine.a

Advice to Patients

Importance of taking the drug exactly as prescribed.180 Advise patients not to double the next dose if a dose is missed; if >4 hours has elapsed since the missed dose, patient should not take the missed dose and should take the next dose as previously scheduled.180

Importance of immediately contacting a clinician if malarial symptoms worsen or do not improve within 2 days of initiating quinine therapy or if fever recurs following completion of antimalarial therapy.180

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.180

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.180

Importance of advising patients of other important precautionary information.180 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Because of serious safety concerns, including fatalities, associated with use of various quinine preparations, FDA ordered firms involved in the marketing of unapproved quinine preparations to discontinue marketing these preparations as of December 11, 2006.182 FDA also ordered that the manufacture of unapproved quinine preparations be discontinued as of February 13, 2007, and that interstate shipment of such preparations be discontinued on June 13, 2007.182185 FDA recommends that individuals using such quinine preparations contact their healthcare provider with any questions or concerns.182

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

164. Centers for Disease Control and Prevention. Health information for international travel, 2010. Atlanta, GA: US Department of Health and Human Services; 2010. Updates available from CDC website ().

186. Centers for Disease Control and Prevention. Guidelines for treatment of malaria in the United States (based on drugs currently available for use in the United States–updated May 18, 2009). From the CDC website. Accessed 2011 Mar 1.